title: Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1.
abstract: BACKGROUND
  We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines.
  
  
  METHODS
  MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin β1 (HRGβ1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation.
  
  
  RESULTS
  Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGβ1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGβ1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGβ1 in all four cell lines.
  
  
  CONCLUSIONS
  These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity.
authors.affiliation: Department of Pharmacology, Radiology & Oncology, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. hutchesonir@cf.ac.uk
authors.forename: Iain R
authors.initials: IR
authors.lastname: Hutcheson
authors.forename: Lindy
authors.initials: L
authors.lastname: Goddard
authors.forename: Denise
authors.initials: D
authors.lastname: Barrow
authors.forename: Richard A
authors.initials: RA
authors.lastname: McClelland
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Francies
authors.forename: Janice M
authors.initials: JM
authors.lastname: Knowlden
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020847:Estrogen Receptor Modulators; D047908:Intracellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D011960:Receptors, Estrogen; D019938:Cyclin D1; C087230:heregulin beta1; D000077267:Fulvestrant; D004958:Estradiol; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4